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In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas

Award Number: U01CA263969
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas - PROJECT SUMMARY Despite the advances made in our understanding of the etiology of pediatric soft tissue sarcomas (STS), the overall survival of those diseases has not significantly improved in over 2 decades. For children with recurrent disease, survival is below 30%, and long-term survivors have an increased burden of disease associated with the curative therapies they received. Therefore, the goal of our research team is to improve the survival and quality of life of children with STS by integrating basic, translational, and clinical research. For the past 10 years, we have consented STS and other solid tumor patients to donate tissue for orthotopic implantation into immunocompromised mice to develop orthotopic patient derived xenografts (O-PDXs). Our O-PDXs have been used for ex vivo high- throughput drug screening and in vivo testing using a standardized preclinical phase I, II, III paradigm. Rhabdomyosarcoma (RMS) is the most common STS in children and genomic studies have shown that rare subsets of clonally related cells can survive treatment and contribute to disease recurrence. Subsequent integrated analyses using transcriptomic, epigenetic and proteomic data showed that RMS tumors retain lineage-specific transcriptional and epigenetic signatures of their developmental origins. More recently, single cell and single nucleus RNA-seq (sc/snRNA-seq) and in vivo lineage-tracing showed that clones of cells can transition through their normal developmental programs. Indeed, single- cell ATAC-seq demonstrated that the cell- and developmental stage–specific super-enhancer activity is correlated with those clonal changes in gene expression. Chemotherapy eliminates the most proliferative tumor cell populations, and the surviving dormant tumor cells rapidly expand and re- establish their developmental hierarchy, which leads to disease recurrence. This is a striking example of the complex cell-intrinsic and -extrinsic signaling within STS and the intricate connection between developmental and oncogenic pathways in childhood cancer. In this proposal, we will perform in vivo testing for 8-10 drugs per year using our STS O-PDX models. The most compelling pathways are developmental kinase pathways (Aim 1), cell stress pathways (Aim 2) and G2/M cell cycle checkpoints (Aim 3). Novel drug combinations will be tested as well as those that include conventional chemotherapy for standard of care. Particular emphasis will be placed on eliminating all the clones in the tumor to improve survival by reducing disease recurrence.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $767,363 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	001	5	7/7/2025	NON-COMPETING CONTINUATION	$767,363
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	4	1/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $767,363

Issue Date FY: 2024 ( Subtotal = $767,363 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	4	7/31/2024	NON-COMPETING CONTINUATION	$767,363
														Subtotal = $767,363

Issue Date FY: 2023 ( Subtotal = $578,635 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	3	7/26/2023	NON-COMPETING CONTINUATION	$578,635
														Subtotal = $578,635

Issue Date FY: 2022 ( Subtotal = $752,016 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	001	2	6/24/2022	NON-COMPETING CONTINUATION	$752,016
2022	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	6/17/2022	NEW	$0
														Subtotal = $752,016

Issue Date FY: 2021 ( Subtotal = $767,363 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	6/24/2021	NEW	$767,363
														Subtotal = $767,363

Grand Total All Awards = $3,632,740

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In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas

Award Number: U01CA263969

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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